Epithelial-to-mesenchymal cell transition (EMT) is a key step in cancer progression and metastasis. However, only a small subpopulation of tumor cells referred to as cancer stem cells (CSCs), or ‘precursor’ metastatic cells, potentially plays a significant role for metastatic tumor initiation and recurrence. CSCs initiate tumors and drive malignant progression by generating and supporting replication of more differentiated non-stem cell progeny (see, for example, Kleffel et al., 2013. Adv Exp Med Biol. 734:145-79; Chen et al., 2013. Acta Pharmacologica Sinica 34:732-740; Páez et al., 2012, Clin Cancer Res. 18(3):645-53). CSCs have been demonstrated to be fundamentally responsible for tumorigenesis, cancer metastasis, tumor relapse, drug resistance, and chemo- and radiotherapy failure. Unfortunately, the mechanisms by which CSCs cause tumor formation and growth and the potential role of CSC-specific differentiation plasticity in tumorigenicity are currently unknown.
Of interest, CSCs share many similar traits with normal stem cells. For example, CSCs have self-renewal capacity, namely, the ability to give rise to additional tumorigenic cancer stem cells, typically at a slower rate than other dividing tumor cells, as opposed to a limited number of divisions. CSCs also have the ability to differentiate into multiple cell types (i.e., they are multipotent), which would explain histological evidence that not only many tumors contain multiple cell types native to the host organ, but also that heterogeneity is commonly retained in tumor metastases.
CSCs express certain cell surface markers as listed for example in Table 1 below:
TABLE 1CSC markers for distinct solid tumor typesBreastColonGliomaLiverLungMelanomaOvarianPancreaticProstateABCB5ALDH1ALDH1ABCG2CD24β-catenin activityCD15CD13ALDH1ABCB5ALDH1ALDH1CD44CD24CD90CD24ABCG2ALDH1CD24CD24CD44CD90CD26CD133CD44CD90CD20CD44CD44CD133CD133CD29α6 integrinCD90CD117CD133CD117CD133α2 β1 integrinHedgehog-GliCD44NestinCD133CD133CD271CD133c-Metα6 integrinactivityα6 integrinCD133CXCR4Trop2CD166NestinLGR5Nodal-Activin
Normal somatic stem cells are naturally resistant to chemotherapeutic agents—they have various pumps (such as multi-drug resistance (MDR) proteins) that pump out drugs, and efficient DNA repair mechanisms. Further, they also have a slow rate of cell turnover while chemotherapeutic agents target rapidly replicating cells. CSCs, being the mutated counterparts of normal stem cells, may also have similar mechanisms that allow them to survive drug therapies and radiation treatment. In other words, conventional chemotherapies and radiotherapies kill differentiated or differentiating cells, which form the bulk of the tumor that are unable to regenerate tumors. The population of CSCs that gave rise to the differentiated and differentiating cells, on the other hand, could remain untouched and cause a relapse of the disease. A further danger for the conventional anti-cancer therapy is the possibility that the treatment of, for instance, chemotherapy, leaves only chemotherapy-resistant CSCs, and the ensuing recurrent tumor will likely also be resistant to chemotherapy.
Consequently, there is a pressing need for the identification of novel approaches that target cytotoxic drug-resistant, tumor-initiating CSCs for preventing and/or treating disease recurrence and distant metastatic spread.